Rheologically modified and osmotically balanced fill material for implant

ABSTRACT

A rheologically modified, osmotically balanced dispersion for an implant for the body. The dispersion includes an osmotic control agent of preferably polyvinylpyrrolidinone, a rheological agent of preferably guar gum, and an antimicrobial. Methods for filling an implant are also disclosed. The osmotic control agent or first polymeric osmotic control agent is present in the dispersion in an amount effective to substantially balance the osmotic pressure of the implant with the osmotic pressure of the portion of the body into which it is implanted. The rheological agent or second polymeric agent forms a three-dimensional network and is present in the dispersion in an amount effective such that the fill material is pseudoplastic. Both the first and second polymeric agents are biocompatible.

BACKGROUND OF THE INVENTION

The present invention relates generally to implants introduced into thebody, particularly to fill material for such implants, and specificallyto rheologically modified fill material for implants.

For implants such as breast and testes prosthesis as well as otherimplants and prosthesis, silicone has been the fill material of choice.However, silicone as a fill material has fallen into disfavor. This hasprompted efforts to find replacements for silicone. These replacementsare often if not always undesirable because such replacements have beenunable to match the feel provided by silicone. The inventors of thepresent invention have investigated the rheological parameters ofcertain fluid formulations in an effort to provide a fill materialhaving the heretofore unmatched feel of silicone. Thus, it is importantto understand some basics of rheology to have an understanding of thepresent invention.

Rheology is the science of the deformation and flow of matter. It isconcerned with the response of materials to mechanical force. Polymerrheology deals with polymeric materials and biorheology deals withbiological fluids.

Deformation is the relative displacement of points of a body and can bedivided into two general types: flow and elasticity. Flow isirreversible deformation; when the stress is removed, the material doesnot revert to its original configuration. Elasticity is reversibledeformation; the deformed body recovers its original shape.

The usual way of defining the rheological properties of a material is todetermine the resistance to deformation. Resistance to deformation ismeasured by two indexes or yardsticks: 1) viscosity (the index oryardstick for flow; viscosity is the resistance to flow of a liquid);and 2) the degree of elasticity (elastic deformation).

A liquid is a material that continues to deform as long as it issubjected to a tensile or shear stress. For a liquid under shear, therate of deformation (shear rate) is proportional to the shearing stress.

Thixotropy is the decrease in viscosity with time when sheared at aconstant shear rate. Rheopexy, a relatively rare occurrence, is theincrease in viscosity of a fluid in response to shear. For example, asto thixotropy, when a shearing action begins, such as when one applies alatex house paint with a brush, the viscosity decreases quickly topermit the paint to be easily brushed to a thin film and provide a shortperiod of time for the brushmarks to level. When the shearing actionstops, such as when the paint leaves the brush and clings to the wall,the viscosity of the latex house paint increases to prevent running andsagging. Thixotropy may be a time dependent effect.

A single fluid may be subject to a number of shear rates. For example, apaint may be pumped during manufacture or immediately prior toapplication (intermediate shear rate), sprayed onto a wall (high shearrate), coalesce and flow to form a uniform film (intermediate to lowshear rate), and sag or run under gravity (low shear rate). A givenliquid or material may work well at one or two of the shear rates, butfail at other shear rates.

SUMMARY OF THE INVENTION

General objects of the present invention include a unique rheologicallymodified dispersion for an implant for a body and unique methods forfilling the implant.

Another object of the present invention is to provide such arheologically modified dispersion which uniquely includes an osmoticcontrol agent.

Another object of the present invention is to provide such arheologically modified dispersion wherein the osmotic control agentuniquely includes a poly-N-vinylamide.

Another object of the present invention is to provide such arheologically modified dispersion wherein the poly-N-vinylamide uniquelyincludes polyvinylpyrrolidinone.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion wherein therheological agent uniquely includes a three-dimensional network.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion wherein thethree-dimensional rheological agent uniquely includes gum.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion wherein thegum uniquely includes a natural gum.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion wherein thenatural gum uniquely includes guar gum or locust bean gum and theirderivatives.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion wherein thegum uniquely includes xanthan and its derivatives.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion wherein thegum uniquely includes a synthetic gum.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion wherein thesynthetic gum uniquely includes poly(vinyl alcohol), polyethylene oxide,polypropylene oxide, polyacrylamide, or copolymers ofpolyvinylpyrrolidinone.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion whichuniquely is a pseudoplastic. Such a pseudoplastic dispersion mimics therheology of body fluid and tissue.

Another object of the present invention is to provide such anosmotically controlled and rheologically modified dispersion in whichuniquely all of the components of the dispersion are biocompatible.Accordingly, even in the worst case scenario in which the implantbursts, little or minimal danger is presented.

An advantage of the present invention is that the fill material of animplant is osmotically balanced with its environment. With an osmoticbalance, the implant retains its desired volume. Such is in contrast toan implant which includes a low osmotic pressure; here, water or anothersolvent flows out of the implant, perhaps causing fold flaw fracture. Ahigh osmotic pressure in the implant may lead to a bursting of theimplant.

Another advantage of the present invention is that the fill material isrheologically modified to be pseudoplastic. This provides a feel orresponsive fill material which mimics body tissue.

These and further objects and advantages of the present invention willbecome clearer in light of the following detailed description of theillustrative embodiments of this invention described in connection withthe drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a perspective, partially exploded view of a breast implant.

FIG. 2 shows a section view of an implant with a dispersion containing adrug to be released over time.

All Figures are drawn for ease of explanation of the basic teachings ofthe present invention only; the extensions of the Figures with respectto number, position, relationship, and dimensions of the parts to formthe preferred embodiment will be explained or will be within the skillof the art after the following description has been read and understood.Further, the exact dimensions and dimensional proportions to conform tospecific force, weight, strength, and similar requirements will likewisebe within the skill of the art after the following description has beenread and understood.

Where used in the various figures of the drawings, the same numeralsdesignate the same or similar parts. Furthermore, when the terms"inner", "outer", and "upper" and similar terms are used herein, itshould be understood that these terms have reference only to thestructure shown in the drawings as it would appear to a person viewingthe drawings and are utilized only to facilitate describing thepreferred embodiments.

DESCRIPTION

In general, the present invention relates to a safe fill material for animplant. The fill material preferably includes water, an osmotic controlagent such as a poly-N-vinylamide or polyvinylimide, a rheological agentsuch as a gum. Optionally, the fill material may include cross-linkersfor the rheological agent (i.e. the thixotrope or gellant) and/or otheradditives such as antioxidants, preservatives such as antimicrobials,wetting agents, and lubricants. The fill material is biocompatible.

Osmotic control agent, for the purposes of the present invention, meansthat which is added to the fill material to prevent or minimize osmosis,i.e. flow of solvent (water) through the membrane of the implant.Osmosis is minimized by providing interior of the implant with anosmotic pressure which is equal to the osmotic pressure of theenvironment outside of the implant. Accordingly, osmotic control agentfurther means that which provides an osmotic pressure similar to thebody or body tissue or fluid or to the portion of the body into whichthe implant is to be located. The most preferred osmotic pressureprovided by the osmotic control agent, when combined with therheological agent of the present invention, is between about 250 andabout 350 milliosmoles.

Still further, the osmotic control agent is a polymer or polymers orcopolymer or copolymers that contributes substantially to the desiredosmotic pressure of between about 250 and 350 milliosmoles. Such asubstantial contribution is made when the polymeric osmotic controlagent is added to the fill material in an amount preferably betweenabout 90% to 99.9% w/w, more preferably between about 95% to 99.9% w/w,and most preferably between about 98% to 99% w/w of the osmotic controlagents. If required, salts may be added to fine tune the osmoticpressure of the implant. These salts preferably include biocompatiblesalts such as sodium chloride, sodium lactate and sodium acetate in anamount of between about 1% and 10% w/w of the osmotic control agents.For radiolucency, sodium lactate and sodium acetate are preferred. Itshould be noted that osmotic pressure is a colligative property thatdepends on the number of solute particles.

Still further, it should be noted that osmotic control agents which arepreferred provide lubricity to the interior wall of the implant. In sum,it is preferred that the osmotic control agent: 1) is a polymer orcopolymer or blend thereof; 2) is present in an amount effective toprovide an osmotic pressure to the implant of between about 250 and 350milliosmoles without the use of salts; and 3) is present in an amounteffective to provide lubricity to the fill material (i.e. to theinterior wall of the implant).

The osmotic control agent is preferably a protective colloid which iswater-soluble or water-dispersable. Examples of preferred colloidsinclude poly-N-vinylamides, poly-N-vinylamide copolymers,polyvinylimides. Poly-N-vinylamide hydrogels are most preferred.

The poly-N-vinylamides may be either linear or cyclic. Examples ofpoly-N-vinylamides prepared from linear derivatives includepoly(acetamide), poly(methylacetamide), poly(ethylacetamide),poly(phenylacetamide), poly(methylpropionamide),poly(ethylpropionamide), poly(methylisobutyramide), andpoly(methylbenzylamide). Poly-N-vinylamides derived from cyclicstructures are more preferred. Examples of these polymers includepolyvinylpyrrolidinone, polyvinylcaprolactam, poly-2-piperidinone, poly5-methyl-2-pyrrolidinone, poly-2,2,5-trimethyl-2-pyrrolidinone, and poly5-methyl-2-pyrrolidinone. Polyvinylpyrrolidinone andpolyvinylcaprolactam are even more preferred with polyvinylpyrrolidinonebeing most preferred.

Polyvinylpyrrolidinone (PVP or povidone orpoly(N-vinyl-2-pyrrolidinone)) is one of the few poly-N-vinylamidesprepared from cyclic structures, if not the only one, available in acommercial quantity. Polyvinylcaprolactam has been commercialized tosome extent.

Poly-N-vinylamide copolymers include poly(vinylpyrrolidinone-co-vinylacetate), poly(vinylpyrrolidinone-co-maleic anhydride),poly(vinylpyrrolidinone-co-methyl methacrylate),poly(vinylpyrrolidinone-co-dimethylaminoethyl methacrylate),poly(vinylpyrrolidinone-co-butyl methacrylate),poly(vinylpyrrolidinone-co-hydroxyethyl methacrylate),poly(vinylpyrrolidinone-co-ethyl acrylate),poly(vinylpyrrolidinone-co-ethylhexyl acrylate),poly(vinylpyrrolidinone-co-acrylic acid),poly(vinylpyrrolidinone-co-acrylamide),poly(vinylpyrrolidinone-co-acrylonitrile,polyvinylpyrrolidinone-co-styrene),poly(vinylpyrrolidinone-co-ethylene), andpoly(vinylpyrrolidinone-co-crotonic acid) and their derivatives.

For the purposes of the present invention, the molecular weight of theosmotic control agent is in the range of preferably about 1,000 to about100,000, more preferably about 1,000 to about 40,000, and even morepreferably about 3,000 to about 20,000, and most preferably about10,000. Poly-N-vinylamides, such as PVP, at molecular weights higherthan about 100,000 may not be excretible from the human body.Poly-N-vinylamides, such as PVP, at weights below about 100,000 may bebioexcretable, with those having molecular weights below 30,000 beingmore likely to be quickly excretable, such as through the human kidney.The molecular weights noted herein are in daltons.

A higher molecular weight of the poly-N-vinylamide, such as PVP,generally relates to a higher degree of polymerization and a greaterintrinsic viscosity. Further, the viscosity of the poly-N-vinylamide(such as PVP) in water generally increases with the solid concentration.

In the fill material according to the present invention, the osmoticcontrol agent is present in the range of preferably from about 0.5% toabout 60%, more preferably from about 2.5% to about 40%, and mostpreferably from about 3.5% to about 20% (w/w).

Such a range of concentration, when combined with one or more of therheological agents of the present invention, provides an osmolarity ofpreferably between about 100 milliosmoles and about 500 milliosmoles,more preferably between about 200 milliosmoles and about 400milliosmoles, and most preferably between about 250 and about 350milliosmoles. It should be noted that such an osmolarity is preferablyobtained without the use of salts. It should further be noted that PVP,when alone in solution without a three dimensional network, does notprovide the desired pseudoplasticity to the solution.

Rheological agent means a material which modifies the normal solutionproperties to increase or decrease its resistance to flow and toincrease or decrease its elasticity. Rheological agent further meansthat which provides a pseudoplasticity to the fill material to theimplant. The fill material of the present invention as a whole ispseudoplastic. In other words, when shear stress is applied to the fillmaterial, the viscosity of the fill material is reduced in proportion tothe amount of shear. Upon release of the shear, total viscosity recoveryof the fill material occurs almost instantaneously.

That the fill material of the present invention is pseudoplastic isadvantageous. This feature of decreased apparent viscosity at high shearrates facilitates mixing, pumping, and pouring. Further, when in thebody, such pseudoplasticity mimics body tissue and fluid, such as thebreast body tissue and fluid. For example, the undesired bounce ofconventional saline implants is minimized.

The rheological agent includes pseudoplastic agents or thixotropicagents. Pseudoplastic agents are preferred.

The rheological agent is preferably a polymer which provides athree-dimensional network within the implant. This three-dimensionalnetwork provides a backbone for the polymeric osmotic control agent,which may contribute in part to the three-dimensional network.

The rheological agent is preferably one which contributes little to theosmotic pressure of the implant. As noted above, osmotic pressure is acolligative property that depends on the number of solute particles.With the present invention, even though it is a massive "particle", thepolymeric rheological agent and its three-dimensional network behaveslike a single particle. Accordingly, it contributes little to theosmotic balance. Conversely, a portion of the polymeric osmotic controlagent contributes to the three-dimensional network, while the remainingportion of the polymeric osmotic control agent dictates the osmoticpressure of the fill material in the implant. It is believed that thecombinations of the present invention are synergistic; that is, theosmotic pressure of the present invention relates little, if at all, toa corresponding amount of an osmotic control agent dispersed only inwater.

Advantageously, it should be noted that the polymeric osmotic controlagents of the present invention move through the three-dimensionalnetwork relatively slowly. In contrast, salts are distributed ratherquickly even in the presence of a three-dimensional network of thepresent invention.

The rheological agent is preferably a gum which is water-dispersible.Examples include gums which are natural polymers and gums which aresynthetic polymers. Examples of natural polymer gums includepolysaccharides, proteins, and natural rubbers and chemically modifiednatural polymers such as hydroxyethylcellulose. Examples of syntheticpolymer gums include poly(vinyl alcohol) and polyethylene oxide.Generally, the rheological agent is added to the fill material in aconcentration of preferably from about 0.05% to about 36%, morepreferably from about 0.1% to about 24%, even more preferably from about0.1% to about 12%, and most preferably from about 0.1% to about 2.0%(w/w).

A gum is a polymeric substance which, in an appropriate solvent orswelling agent, form highly viscous dispersions or gels at low, drysubstance content. Gums may or may not be water-soluble.

The gum preferably is a water soluble polysaccharide (glycan). Examplesinclude seed gums such as corn starch, guar gum, and locust bean gum;tuber and root gums such as potato starch and tapioca starch; seaweedextracts such as algin, carageenan, agar, and furcellaran; plantextracts such as pectin; exudate gums such as gum arabic; fermentation(microbial) gums such as xanthan (qv), dextran (qv) and welan(polysaccharide S-130); and derived gums such as carboxymethylcellulose,hydroxyalkylmethylcellulose, methylcellulose, starch acetate, starchphosphate, hydroxyethylstarch, hydroxypropylstarch, oxidized starches,and dextrinized starches. Seed gums are most preferred. Of the seedgums, guar gum is most preferred. The glycan is added to the fillmaterial in a concentration of preferably from about 0.1% to about 25%,more preferably from about 0.1% to about 15%, and most preferably fromabout 0.01% to about 10% (w/w).

Examples of gums which are galactommannans (a polymer of D-galactose andD-mannose) include guaran (the purified polysaccharide from guar gum),locust bean gum, and tara gum. Of these guaran is preferred. Guar gum,locust bean, and tara gum also means, for the purposes of the presentinvention, their blends, and the endosperms, high purity splits,derivatives, granules, and powders of such gums. Examples of guarderivatives include hydroxypropyl-, hydroxyethyl-, sodiumcarboxymethyl-, sodium carboxymethylhydroxypropyl-, and2-hydroxypropyl(trimethyl)ammonium guar gums.

The galactommannan is added to the fill material in a concentration ofpreferably from about 0.05% to about 6%, more preferably from about 0.1%to about 4.0%, and most preferably from about 0.1% to about 2% (w/w).

Chemically modified natural polymers or derived gums preferably includecellulose derivatives such as an hydroxyalkylcellulose. Examples ofhydroxyalkylcellulose include carboxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,ethylhydroxyethylcellulose. The derived gum is added to the fillmaterial in a concentration of preferably from about 0.5% to about 30%,more preferably from about 5% to about 25%, and most preferably fromabout 8% to about 15% (w/w).

Xanthan (or xanthan gum) may be used as the sole rheological agent ofthe present invention or in combination with locust bean and/or guargum. When used alone, xanthan is added to the fill material in aconcentration of preferably from about 0.05% to about 6%, morepreferably from about 0.1% to about 4.0%, and most preferably from about0.1% to about 2.0% (w/w).

The amount of xanthan in locust bean gum or in a locust bean/guar gumblend may be between about 1% and about 99% w/w. The amount of locustbean or guar gum in such a blend may be between about 1% and about 99%w/w. The xanthan and/or locust bean and/or guar blend is added to thefill material in a concentration preferably from about 0.05% to about6%, more preferably from about 0.1% to about 4.0%, and most preferablyfrom about 0.1% to about 2% (w/w).

Examples of synthetic polymer gums, where such form biocompatiblewater-dispersable and water-soluble gums, include poly(vinyl alcohol),polyethers such as the poloxamers polyethylene oxide and polypropyleneoxide, polyacrylamide, their copolymers and blends, and copolymers ofpoly-N-vinylamides, including copolymers of polyvinylpyrrolidinone suchas poly(N-1-vinylpyrrolidone)-co-2-methylaminoethylmethacrylate,poly(1-vinylpyrrolidone)-co-acrylic acid, andpoly(1-vinylpyrrolidone)-co-vinylacetate. As to polyethylene oxide andpolypropylene oxide and their copolymers and blends, the totality of theTautvydas et al. U.S. Pat. No. 5,407,445 is hereby incorporated byreference.

The synthetic polymer gum is added to the fill material in aconcentration of preferably from about 0.5% to about 60%, morepreferably from about 0.5% to about 40%, and still more preferably fromabout 0.5% to about 20% (w/w). Still further, in the case ofpolyethylene oxide or polypropylene oxide, the most preferred range isabout 0.6% to about 5.0% of the fill material. Of the biodegradablesynthetic polymers, poly(vinyl alcohol) and polyethylene oxide arepreferred.

The gum of the present invention preferably includes those gums whichhave been identified as the safest gums for an implant in the body. Suchgums include guar, a cellulose derivative (selected from the group ofcarboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,ethylhydroxyethylcellulose), xanthan, a xanthan/locust bean mixture,polyethylene oxide, and poly(vinyl alcohol). Guar, polyethylene oxide,and poly(vinyl alcohol) are most preferred.

It should be noted that it is preferred that the rheological agent ofthe present invention is one which contributes little, if any, to theosmotic pressure of the implant fill material. As osmolarity is afunction of the number of particles, it is preferred that therheological agent have a sufficiently high molecular weight. Guar, forexample, typically includes a molecular weight between about 200,000 andabout 240,000. Locust bean gum typically includes a molecular weightbetween about 300,000 and 360,000. The compound (or compounds) formingthe three-dimensional network includes a molecular weight preferablybetween about 4,000 and 4,000,000, and more preferably between about100,000 and 600,000.

An example of a biocompatible compound which forms a three-dimensionalnetwork but which is neither a gum nor a polymer is gelatin. Gelatin isa heterogeneous mixture of water-soluble proteins of high averagemolecular weight. Gelatin is not found in nature but is derived fromcollagen. Gelatin may be obtained by boiling skin, tendons, ligaments,bones, etc. with water.

Examples of means for preventing microbial growth include irradiation(gamma radiation) of the fill material and antimicrobial preservativessuch as benzoates and parabens, and non food grade preservatives. Thepreservatives are added to the fill material in concentrations at orless than about 1% w/w, or more preferably at or less than about 0.5%w/w, and still more preferably at or less than 2.5 w/w.

It should be noted that the rheological agents of the present inventioninclude those rheological agents which have been irradiated prior tointroduction into the dispersion or formation of gum. Thesepre-irradiated rheological agents include pre-irradiated guar or xanthangums. As to pre-irradiated rheological agents, the totality of theBurgum U.S. Pat. No. 5,273,767 is hereby incorporated by reference.

Optionally, the fill material includes a reactant such as across-linking agent for the rheological agent. These cross-linkingagents include Al₂ (SO₄)₃ and its analogs, borates such as borax, boricacid and its analogs, titonates, chrome complexes, zirconium, andcalcium compounds. Generally, these cross-linking agents are added tothe fill material in a concentration of preferably at or less than 1%w/w and more preferably at or less than 1% of the concentration of therheological agent. Cross-linking or hydrogen bonding in thethree-dimensional network of the present fill material may provide aviscoelastic fill material.

It should be noted that one object of the present invention is toprovide a safer fill material for an implant. A safer fill material isone which includes the least possible amount of nontoxic foreigncomponents.

It should be noted that the lubricity of the fill material is preferablyprovided by the polymeric osmotic control agent, such as the colloid,the poly-N-vinylamide, or polyvinylpyrrolidinone. The amount of thepolymeric osmotic control agent effective to provide an osmotic pressureto the implant of between about 250 and 350 milliosmoles is more thanrequired to provide lubricity to the fill material.

The viscosity, or apparent viscosity, of the fill material is in therange of preferably between about 100 and 20,000 centipoise, morepreferably between about 200 and about 10,000 centipoise, and mostpreferably between about 400 and about 500 centipoise.

The implant according to the present invention may be a breast or testesprosthesis, a penile implant, or an implant containing a drug to bedispersed over time. The shell of the implant may be permeable orimpermeable. For example, the shell may be permeable to water vapor ormay be impermeable to water vapor, or may be permeable to other fluidsor compounds such as drugs or pharmaceutical agents. Examples of shellswhich are permeable to water vapor include the shell set forth in U.S.patent application Ser. No. 08/473,284, filed Jun. 7, 1995, the totalityof which is hereby incorporated by reference. Examples of shells whichare permeable to water vapor include the conventional silicone orpolyurethane shell.

A breast implant is shown in FIG. 1. It includes a shell 11, a fillmaterial 12 of the present invention, and a closure or joint 13 forclosing the shell 11 and Sealing the fill material therein. The closure13 is a room temperature vulcanized silicone button seal. The closure 13is formed of the same material as the shell 11 and includes an innerdisk shaped silicone layer 20 having a greater diameter than the outerdisk shaped layer 22 such that an annular portion 24 of the inner layer20 extends beyond the outer layer 22. The outer surface of the annularportion 24 is bonded via a vulcanized weld to the inner surface of theshell 11. The outer disk shaped layer 22 has a diameter substantiallyequal to the diameter of the opening 26 formed by the mandrel in themanufacture of the shell 11. A leaf valve assembly or primary closure 28is fixed to the inner surface of the disk shaped portion 20. The leafvalve assembly 28 includes an outlet 30 and an inlet disposed adjacentto the center of the disk shaped portion 20. The opposing flap sides ofthe leaf valve assembly 28 cling together to minimize passage of fluidthrough the assembly 28. After the closure 13 has been vulcanized to theshell 11 to close the shell 11, a needle filled with the fillingmaterial 12 penetrates the closure 13 and extends into the inlet of theleaf assembly 28. The needle is then operated to push the fill material12 into the shell 11. After the shell has been filled, a pocket of airtypically exists in the upper portion of the shell 11. This air may bewithdrawn by operation of the needle. The hole formed in the center ofthe closure 13 by the penetration of the needle is then sealed with abiocompatible silicone to form the domed button seal or secondaryclosure 32. It should be noted that the closure 13 may alternativelyinclude a valve such as compression valve or septa. As noted above, theshell 11 may be of a material which is permeable or impermeable to watervapor. The shell 11 may be silicone, polyurethane, or anotherelastomeric material.

FIG. 2 shows an implant 40 containing the fill material 12 and a drug orpharmaceutical or therapeutic agent 42 to be dispersed over time. Theimplant 40 includes a spherical ovoid or coin-like shell 44 which ispermeable or semipermeable relative to the agent 42. When the shell issilicone, examples of the agent include silicone permeable hormones suchas progesterone, Estradiol including 17-B-Estradiol, Melatonin, andLevonorgestrel, silicone permeable narcotic analgesics such as Fentanyland morphine sulfate, and silicone permeable antianginal agents orvasodilators such as nitroglycerin.

Procedures for filling the implants include the following method. Thetemperature of double distilled water is adjusted to 35° F. (1.67° C.).The components are then preferably added to the double distilled waterin the following order: the preservative if desired, the cross-linkingagent if desired, the osmotic control agent, and then the rheologicalagent. Then the dispersion is agitated and the temperature of thedispersion is permitted to rise in an environment at room temperatureuntil the desired swelling has occurred. The dispersion is then injectedinto the implant. The implant is then rotated such that the dispersionremains uniformly dispersed, thereby allowing the rheological agent tofully hydrate (and cross-link if a cross-linking agent has been added toprovide a three dimensional network if the rheological agent alone doesnot provide such).

It should be noted that "biocompatible" means that which remains inunchanged form in the body without causing adverse reaction, that whichmay be metabolized, and/or that which may be excreted without beingmetabolized.

It should further be noted that the fill material of the presentinvention is radiolucent. The fill material is not radiographicallydense, nor does the fill material result in under-exposure of x-rayfilm. The fill material includes an optical density from about 1.2 toabout 1.3 and an x-ray penetrance of from about 9.2 to about 30milliroentgens. The osmotic control agents and rheological agents of thepresent invention include elements with relatively low atomic numberswhich do not interfere with radiolucency.

EXAMPLE 1

(PVP and guar)

Eight hundred (800) grams of high purity water were mixed with 200 g ofPVP [poly(2-vinylpyrrolidone), Povidone K-17, (ISP Povidone C-15)] atroom temperature to form a yellow liquid. Two and one half grams ofmethyl-4-hydroxybenzoate and two and one half grams ofpropyl-4-hydroxybenzoate were added to the PVP solution with vigorousstirring. Fifteen grams of Jaguar 8600 guar gum (Rhone-Poulenc,Specialty Chemical Division, Prospect Plains Road, Cranberry N.J.) wereadded by carefully dispersing the gum into the vortex of a rapidly (ca2,000 rpm) stirring laboratory mixer to form a responsive gel.

EXAMPLE 2

(PVP and guar)

Eight hundred (800) grams of high purity water were mixed with 200 g ofPVP (poly(2-vinylpyrrolidone)), at room temperature to form a yellowliquid. Two and one half grams of methyl-4-hydroxybenzoate and two andone half grams of propyl-4-hydroxybenzoate were added to the PVPsolution with vigorous stirring. Thirty grams of Jaguar 8600 guar gumwere added by carefully dispersing the gum into the vortex of a rapidly(ca 2,000 rpm) stirring laboratory mixer to form a responsive gel.

EXAMPLE 3

(PVP and guar)

Eight hundred (800) grams of high purity water were mixed with 200 g ofPVP (poly(2-vinylpyrrolidone)) at room temperature to form a yellowliquid. Two and one half grams of methyl-4-hydroxybenzoate and two andone half grams of propyl-4-hydroxybenzoate were added to the PVPsolution with vigorous stirring. Forty-five grams of Jaguar 8600 guargum were added by carefully dispersing the gum into the vortex of arapidly (ca 2,000 rpm) stirring laboratory mixer to form a responsivegel.

EXAMPLE 4

(PVP and guar)

Eight hundred (800) grams of high purity water were mixed with 200 g ofPVP (poly(2-vinylpyrrolidone)) at room temperature to form a yellowliquid. Two and one half grams of methyl-4-hydroxybenzoate and two andone half grams of propyl-4-hydroxybenzoate were added to the PVPsolution with vigorous stirring. Fifty-five grams of Jaguar 8600 guargum were added by carefully dispersing the gum into the vortex of arapidly (ca 2,000 rpm) stirring laboratory mixer to form a responsivegel.

EXAMPLE 5

(PVP and pectin)

Two hundred grams of a 20% w/w solution of PVP(poly(2-vinylpyrrolidone)) (with a base of high purity water) were mixedwith Carex F/G Arabinose Galactan (a pectin from the larch tree) byadding the Galactan to the vortex of rapidly stirred water. Thetemperature was raised slowly, over the course of one hour, to 97° C.with moderate stirring to form a responsive gel.

EXAMPLE 6

(PVP and gelatin)

Gelatin (Knox household gelatin) was added to a 20% (w/w) PVP(poly(2-vinylpyrrolidone)) solution as described in Example 1. Thedispersion was heated until all the gelatin dissolved forming a clearsolution. Upon cooling a responsive gel formed. Several concentrationswere prepared using this same technique to provide gels of varyingconsistency.

EXAMPLE 7

(PVP and polyethylene oxide)

Four hundred grams of deionized water and one hundred grams of PVP(poly(2-vinylpyrrolidone)) were mixed with vigorous stirring. To thissolution three grams of Polyox 303 (polyethylene oxide, Union Carbide)were added. The rapid formation of a responsive gel was noted.

EXAMPLE 8

(PVP and polyethylene oxide)

Four hundred grams of deionized water and one hundred grams of PVP(poly(2-vinylpyrrolidone)) were mixed with vigorous stirring. To thissolution three grams of Polyox 303 (polyethylene oxide, Union Carbide)were added. The rapid formation of a responsive gel was noted.

EXAMPLE 9

(PVP and polyethylene oxide)

Four hundred grams of deionized water and one hundred grams of PVP(poly(2-vinylpyrrolidone)) were mixed with vigorous stirring. To thissolution six grams of Polyox 303 (polyethylene oxide, Union Carbide)were added. The rapid formation of a responsive gel was noted.

EXAMPLE 10

(PVP and polyethylene oxide)

Eight hundred grams of deionized water and one hundred grams of PVP(poly(2-vinylpyrrolidone)) were mixed with vigorous stirring. To thissolution twenty-five grams of Polyox 303 (polyethylene oxide, UnionCarbide) were added. The rapid formation of a responsive gel was noted.

EXAMPLE 11

(PVP and PVP copolymer)

Two hundred grams of a 20% solution ofpoly(N-1-vinylpyrrolidone)-co-2-methylaminoethylmethacrylate were mixedwith two hundred and fifty-eight grams of high purity water to form aresponsive gel. Thirty six grams of PVP (poly(2-vinylpyrrolidone)) wereadded to the mixture. Upon standing a responsive viscous gel was formed.

EXAMPLE 12

(PVP and PVP copolymer)

Nine hundred forty-nine grams of 20% (w/w) PVP(Poly(2-vinylpyrrolidone)) solution were mixed with fifty-one grams ofpoly(1-vinylpyrrolidone)-co-acrylic acid were mixed together and heatedat 70° C. for one hour to form a responsive gel.

EXAMPLE 13

(PVP and PVP copolymer)

One hundred grams of Poly(1-vinylpyrrolidone)-co-vinylacetate were mixedwith eight hundred and thirty grams of deionized water and mixed withvigorous stirring. Seventy grams of PVP (poly(2-vinylpyrrolidone)) wereadded to the mixture with vigorous stirring to form a responsive gel.

Thus since the invention disclosed herein may be embodied in otherspecific forms without departing from the spirit or generalcharacteristics thereof, some of which forms have been indicated, theembodiments described herein are to be considered in all respectsillustrative and not restrictive. The scope of the invention is to beindicated by the appended claims, rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalents of the claims are intended to be embraced therein.

We claim:
 1. A safe, rheologically modified, osmotically balanced,biocompatible, lubricating, water based, implant fill material for animplant for the body, the implant having an inner face, the implant fillmaterial comprising, in combination: an aqueous dispersion whichcomprises a first polymeric agent and a second polymeric agent, with thefirst polymeric agent comprising a polymeric osmotic control agent andwith the second polymeric agent comprising a polymeric rheological agentselected from the group consisting of guar gum and guar gum derivatives,with the polymeric osmotic control agent being present in the dispersionin an amount effective to substantially balance the osmotic pressure ofthe implant with the osmotic pressure of the portion of the body intowhich it is implanted and such that the dispersion has an osmolarity ofbetween about 250 and about 350 milliosmoles, with the osmotic controlagent further being a lubricant to lubricate an inner face of theimplant, with the polymeric rheological agent forming athree-dimensional network and being present in the dispersion in anamount effective such that the fill material forms a responsive gel,with the polymeric osmotic control agent being movable through thethree-dimensional network, and with the fill material beingbiocompatible.
 2. The implant fill material of claim 1 wherein theosmotic control agent comprises a poly-N-vinylamide.
 3. The implant fillmaterial of claim 1 wherein the osmotic control agent is selected fromthe group consisting of poly-N-vinylamides, poly-N-vinylamidecopolymers, and polyvinylimides.
 4. The implant fill material of claim 3wherein the poly-N-vinylamide is derived from a cyclic structure.
 5. Theimplant fill material of claim 4, wherein the poly-N-vinylamide isselected from the group consisting of polyvinylpyrrolidinone,polyvinylcaprolactam, poly(2-piperidinone),poly(5-methyl-2-pyrrolidinone), poly(2,2,5-trimethyl-2-pyrrolidinone),and poly(5-methyl-2-pyrrolidinone).
 6. The implant fill material ofclaim 5, wherein the poly-N-vinylamide is polyvinylpyrrolidinone.
 7. Theimplant fill material of claim 6, wherein the polyvinylpyrrolidinone hasa molecular weight from about 3,000 to about 30,000 daltons.
 8. A safe,rheologically modified, osmotically balanced, biocompatible,lubricating, water based, implant fill material for an implant for thebody, the implant having an inner face, the implant fill materialcomprising, in combination: an aqueous dispersion which comprises afirst polymeric agent and a second polymeric agent, with the firstpolymeric agent comprising a polymeric osmotic control agent and withthe second polymeric agent comprising a polymeric rheological agent,with the polymeric osmotic control agent being present in the dispersionin an amount effective to substantially balance the osmotic pressure ofthe implant with the osmotic pressure of the portion of the body intowhich it is implanted, with the osmotic control agent further being alubricant to lubricate an inner face of the implant, with the polymericrheological agent forming a three-dimensional network and being presentin the dispersion in an amount effective such that the fill material ispseudoplastic, with the polymeric osmotic control agent being movablethrough the three-dimensional network, and with the fill material beingbiocompatible, wherein the polymeric osmotic control agent comprisespolyvinylcaprolactam.
 9. The implant fill material of claim 8 whereinthe osmotic control agent is present in an amount effective to providethe dispersion with an osmolarity of between about 250 and about 350milliosmoles.
 10. The implant fill material of claim 1 wherein the fillmaterial is radiolucent.
 11. The implant fill material of claim 1wherein the dispersion comprises an antimicrobial to minimize microbialgrowth.
 12. The implant fill material of clam 1 wherein the dispersionis irradiated to minimize microbial growth.
 13. An implant fill materialcomprising, in combination: an aqueous dispersion ofpolyvinylpyrrolidinone, and guar gum or a derivative of guar gum, withthe polyvinylpyrrolidinone and guar gum or the derivative of guar gumbeing present in an amount effective such that the dispersion has anosmolarity of between about 250 and about 350 milliosmoles and ispseudoplastic.
 14. An implant fill material comprising, in combination:an aqueous dispersion comprising first and second polymeric agents, withthe first polymeric agent comprising a poly-N-vinylamide and with thesecond polymeric agent comprising guar gum or a derivative of guar gumand forming a water dispersible biodegradable three dimensional network,with the poly-N-vinylamide being present in an effective amount suchthat the dispersion has an osmolarity of between about 250 and about 350milliosmoles and with the second polymeric agent being present in aneffective amount such that the dispersion forms a responsive gel.
 15. Animplant fill material comprising, in combination: an aqueous dispersionof polyvinylpyrrolidinone, and guar gum or a derivative of guar gum,with the polyvinylpyrrolidinone and guar gum or the derivative of guargum being present in an amount effective such that the dispersion has anosmolarity of between about 250 and about 350 milliosmoles and forms aresponsive gel.